LCK-PHOSPHORYLATED HUMAN KILLER CELL-INHIBITORY RECEPTORS RECRUIT ANDACTIVATE PHOSPHATIDYLINOSITOL 3-KINASE

HLA-specific killer cell inhibitory receptors (KIR) are thought to imp ede natural killer (NK) and T cell activation programs through recruit ment of the SH2 domain-containing tyrosine phosphatases, SHP-1 and SHP -2, to their cytoplasmic tails (CYT). To identify other SH2 domain-con taining proteins that bind KIR CYT, we used the recently described yea st two-bait interaction trap and a modified version of this system, bo th of which permit tyrosine phosphorylation of bait proteins, Using th ese systems, we show that KIR CYT, once phosphorylated by the src-fami ly tyrosine kinase LCK, additionally bind the p85 alpha regulatory sub unit of phosphatidylinositol (PI) 3-kinase. Furthermore, we show that in an NK cell line, NK3.3, cross-linking of KIR results in recruitment of p85 alpha to KIR and activation of PI 3-kinase lipid kinase activi ty. One consequence of KIR coupling to PI 3-kinase is downstream activ ation of the antiapoptotic protein kinase AKT. Therefore, in addition to providing negative signals, KIR may also contribute positive signal s for NK and T cell growth and/or survival.